Addiction is a chronic relapsing disorder. Despite extended abstinence, addicts may experience intense craving in response to drug re-exposure, cues or stress. How do strong cravings re-emerge and what are the neurobiological triggers? Nucleus accumbens (NAc) is a key target of addictive drugs in the mammalian brain. Animal models implicate NAc in enduring vulnerability to reinstatement of drug seeking. Although reinstatement involves plasticity in NAc AMPA-type glutamate receptors (AMPARs), the identity of this plasticity is unclear. Combining rodent reinstatement models with NAc whole-cell recordings in an ex vivo preparation, we identified a putative neural substrate for relapse. During cocaine abstinence, a cocaine prime, in vivo or in vitro, induces AMPAR long-term depression (re-exposure LTD), indicating that NAc AMPAR plasticity in response to environmental stimuli during abstinence is highly dynamic. We hypothesize that re- exposure LTD provides a synaptic gateway for reinstatement. To test this, we will directly measure and manipulate NAc AMPAR plasticity in drug-, cue- and stress-primed reinstatement and incubation models. In addition, priming in a dish gives us a tractable model system to study molecular mechanisms of reinstatement-linked plasticity. We hypothesize that propping up NAc AMPAR function during abstinence may be a useful tool in combating relapse. PUBLIC HEALTH RELEVANCE: Using a combination of rodent behavioral models and advanced cellular electrophysiological techniques, we will investigate the relationship between synaptic plasticity and drug relapse. We have identified a putative neurobiological relapse trigger in the nucleus accumbens-a region of the mesolimbic dopamine circuit that is critical in addiction. We expect our studies to inform new strategies for relapse prevention and treatment.